Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH:23]=O)[CH2:6][O:5][C:4]([C:7]2[CH:8]=[N:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:21][CH2:20][CH2:19][CH:18]3[CH3:22])=[CH:11][CH:12]=2)=[N:3]1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClC(Cl)C>[CH3:1][C:2]1([CH2:23][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:21][CH2:20][CH2:19][CH:18]3[CH3:22])=[N:9][CH:8]=2)=[N:3]1
Reactant: C1CCNC1
Reactant: CC1CCCN1CCCOc1ccc(C2=NC(C)(C=O)CO2)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O
Product: CC1CCCN1CCCOc1ccc(C2=NC(C)(CN3CCCC3)CO2)cn1
Temperature: 22 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
A solution of 4-methyl-2-{6-[3-(2-methylpyrrolidin-1-yl)propoxy]pyridin-3-yl}-4,5-dihydro-1,3-oxazole-4-carbaldehyde ax57 (273 mg, ca. 80% pure, ca. 0.66 mmol) in dichloroethane (4 ml) is treated with pyrrolidine (0.27 ml, 3.28 mmol) and sodium triacetoxyborohydride (0.35 g, 1.64 mmol), and the turbid solution is stirred at 22° C. overnight. Fresh pyrrolidine (0.145 ml, 1.64 mmol) and sodium triacetoxyborohydride (0.35 g, 1.64 mmol) are added and the solution is stirred for an additional 2 hours at room temperature. Water is then added and the mixture stirred vigorously for 5 minutes. Extraction is performed with dichloromethane until the organic extract does not contain significant UV-active spots. The combined organic layers are dried over sodium sulfate and concentrated to yield a brown oil. The product is purified by chromatography over silicagel (eluent: gradient 10 to 20% triethylamine in 90 to 80% hexanes) to afford 66 mg of 5-[4-methyl-4-(pyrrolidin-1-ylmethyl)-4,5-dihydro-1,3-oxazol-2-yl]-2-[3-(2-methylpyrrolidin-1-yl)propoxy]pyridine 33.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].N1C=CN=C1.[C:13]([Si:17]([CH3:20])([CH3:19])Cl)([CH3:16])([CH3:15])[CH3:14].O>O1CCCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][Si:17]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:20])[CH3:19]
Reactant: OCCCCCBr
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCCCBr
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.1 %

Procedure:
A solution of 28 g of the crude 5-bromo-1-pentanol in 144 ml of tetrahydrofuran is treated with 24 g of imidazole. A solution of 30.3 g of tert-butyldimethyl-chlorosilane in 46 ml of tetrahydrofuran is then added dropwise and the mixture is stirred at room temperature for 4 hours. The reaction mixture is poured into water, extracted by shaking with diethyl ether, and the organic phase is washed 4 times with water, dried over sodium sulphate and concentrated. The crude product is chromatographed on silica gel using hexane/diethyl ether. 42 g of the title compound are obtained as a colourless liquid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][C:3]=1[NH2:4].FC(F)(F)S(O[C:25]1[C:36]([CH3:37])=[N:35][C:28]2[N:29]=[C:30]([S:33][CH3:34])[N:31]=[CH:32][C:27]=2[CH:26]=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([C:25]2[C:36]([CH3:37])=[N:35][C:28]3[N:29]=[C:30]([S:33][CH3:34])[N:31]=[CH:32][C:27]=3[CH:26]=2)=[CH:5][C:3]=1[NH2:4]
Reactant: CSc1ncc2cc(OS(=O)(=O)C(F)(F)F)c(C)nc2n1
Reactant: Cc1cc(F)c(N)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CSc1ncc2cc(-c3cc(N)c(F)cc3C)c(C)nc2n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
Combine 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (370 mg, 1.474 mmol), 7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl trifluoromethanesulfonate (500 mg, 1.474 mmol) and K2CO3 (611 mg, 4.42 mmol) in dioxane (12 mL) and H2O (3 mL), sparge with argon, treat with Pd(PPh3)4 (85 mg, 0.074 mmol) and heat to 60° C. for 3 h. Cool the mixture to RT, stir overnight, treat with EtOAc and wash with brine. Filter the mixture, wash the organic layer again with brine, dry over Na2SO4, concentrate to dryness and purify via reverse-phase chromatography (MeCN/H2O with 0.1% TFA). Combine fractions, remove the organics under reduced pressure and neutralize the aqueous residue with saturated. NaHCO3. Extract the mixture with EtOAc (2×), wash the combined organics with brine, dry over Na2SO4 and concentrate to dryness to afford the title compound as an amorphous solid (373 mg, 81%). MS (m/z): 315.1 (M+1).
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([C:19]1[N:20]2[CH:23]([S:24][CH2:25][C:26]=1[CH3:27])[CH:22]([NH:28][C:29]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:21]2=[O:48])([OH:18])=[O:17].CCC=CCCCC>C(#N)C>[CH:7]([O:17][C:16]([C:19]1[N:20]2[CH:23]([S:24][CH2:25][C:26]=1[CH3:27])[CH:22]([NH:28][C:29]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:21]2=[O:48])=[O:18])([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C2SC1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Agent: CCC=CCCCC
Solvent: CC#N
Product: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C2SC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
A solution of diphenyldiazomethane (12.3 g) in acetonitrile (200 cc) is added, in the course of 15 minutes, to a suspension of a mixture (28.8 g) of 2-carboxy-3-methyl-8-oxo-7-tritylamino-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (40%) and its oct-3-ene isomer (60%) in acetonitrile (500 cc), and the reaction mixture is then stirred for 2 hours at 25° C. The solvent is evaporated under reduced pressure (40 mm Hg) at 30° C. and the oily residue is redissolved in ethyl acetate (500 cc). The solution is washed successively with normal hydrochloric acid (until colourless), with a saturated sodium bicarbonate solution (3×100 cc), with water (100 cc) and with a saturated sodium chloride solution (100 cc), and is then dried and concentrated to dryness, to give a mixture (35.4 g) of 2-benzhydryloxycarbonyl-3-methyl-8-oxo-7-tritylamino-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (40%) and its oct-3-ene isomer (60%), in the form of a cream-coloured froth.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][N:11]([CH3:19])[C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1.CC(O)=O>CCO>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[N:18]/[C:15]2[CH:16]=[CH:17][C:12]([N:11]([CH3:19])[CH3:10])=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CN(C)c1ccc(N)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: CN(C)c1ccc(/N=C/c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 73.5 %

Procedure:
To a mixture of 4-chloro-benzaldehyde (1.55 g, 11.0 mmol) and N,N-dimethyl-benzene-1,4-diamine (1.5 g, 11.0 mmol) in EtOH (15 ml) was added a catalytic amount of AcOH (0.063 ml, 1.1 mmol) at RT. The reaction mixture was heated at reflux and stirred for 14 h during which time precipitation took place. After cooling to RT, the slurry was filtered and washed with heptane. The solid was collected and dried under high vacuum to yield the title compound (2.09 g, 8.08 mmol, 73%) as a brownish solid. 1H NMR (400 MHz, CDCl3): 3.01 (s, 6H), 6.78 (m, 2H), 7.29 (m, 2H), 7.44 (m, 2H), 7.84 (m, 2H), 8.49 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[Mn]([O-])(=O)(=O)=[O:10].[K+].[OH2:15]>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:15]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O
Reactant: Cc1ccncc1Br
Agent: [K+]
Product: O=C(O)c1ccncc1Br
Reaction time: 36 h

Procedure:
12.9 g (75 mmole) of 3-bromo-4-picoline was added to a purple solution of 23.7 g (0.15 mole) of potassium permanganate in 600 mL of water. This mixture was vigorously stirred 36 hrs. at 45° C. The resulting black solid was filtered and washed with 4×50 mL of hot water. The filtrate was concentrated to ~50 mL. A viscous liquid with black solid resulted. This was filtered through celite, which was washed with 3×20 mL of water. 150 mL of ice cold 2N hydrochloric acid was added. The resulting voluminous white precipitate was filtered and the solid was dried in vacuo to give 3-bromoisonicotinic acid as white powder.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[Cl:6][C:7]1[CH:35]=[CH:34][C:10]([CH2:11][C:12]2[N:13]=[C:14]([O:30][CH2:31][CH2:32][CH3:33])[C:15]3[N:20]=[C:19]([C:21]4[CH:26]=[C:25]([CH3:27])[C:24]([OH:28])=[C:23]([CH3:29])[CH:22]=4)[O:18][C:16]=3[N:17]=2)=[CH:9][CH:8]=1.[OH-].[Na+].C(OCC)(=O)C>C(O)(C)C.O>[Cl:6][C:7]1[CH:35]=[CH:34][C:10]([CH2:11][C:12]2[N:13]=[C:14]([O:30][CH2:31][CH2:32][CH3:33])[C:15]3[N:20]=[C:19]([C:21]4[CH:22]=[C:23]([CH3:29])[C:24]([O:28][CH2:1][CH:3]5[CH2:4][O:5]5)=[C:25]([CH3:27])[CH:26]=4)[O:18][C:16]=3[N:17]=2)=[CH:9][CH:8]=1
Reactant: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(O)c(C)c3)nc12
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCC4CO4)c(C)c3)nc12
Temperature: 50 °C

Procedure:
A mixture of 218.5 μl of epichlorohydrine and 370 mg of 4-[5-(4-chloro-benzyl)-7-propoxy-oxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethyl-phenol in 4.4 ml of isopropanol and 1.2 ml of an aqueous 3 N sodium hydroxide solution was heated to 50° C. for 8 h. Then ethyl acetate and water were added and the layers were separated. The organic layer was extracted with water, dried over sodium sulfate, filtered and evaporated in vacuo to give 410 mg of the crude title compound which was used in the next step without further purification.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1.C(OCC)(OCC)OCC.[CH:20]1[CH:25]=CC(C2C=CC=CC=2)=C[CH:21]=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[N:4]1[C:5]2[C:6](=[N:9][CH:21]=[CH:20][CH:25]=2)[CH:7]=[CH:8][CH:3]=1
Reactant: c1ccc(-c2ccccc2)cc1
Reactant: COc1ccc(N)cn1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOC(OCC)OCC
Product: c1cnc2cccnc2c1

Procedure:
An alternative synthetic sequence to obtain the key intermediate E is described in Scheme 2. Commercially available 2-methoxy-5-aminopyridine F is converted by heating in the presence of ester B and triethyl orthoformate to the condensation product G as a mixture of olefin isomers (Scheme 2). Intermediate G is added to hot Dowtherm™ A to facilitate the ring closure and to yield the 1,5-naphthyridine H. Demethylation at the 6-position of H is conducted by treatment with trimethylsilyl chloride and sodium iodide in refluxing acetonitrile to give intermediate I, which may be used, without purification, for the reaction with phosphorus oxychloride to provide the key intermediate E (Scheme 2).
Reaction SMILES: [OH:1][C@@H:2]([C:19]1[C:20]([CH3:29])=[C:21]2[C:25](=[CH:26][CH:27]=1)[C:24](=[O:28])[O:23][CH2:22]2)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12]C(C)(C)C)=[O:11])[CH2:6][C@H:5]1[CH2:17][OH:18].FC(F)(F)C(O)=O.C(N(CC)CC)C.ClC(O[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=O>C(Cl)Cl>[OH:1][C@@H:2]([C:19]1[C:20]([CH3:29])=[C:21]2[C:25](=[CH:26][CH:27]=1)[C:24](=[O:28])[O:23][CH2:22]2)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:11])[CH2:6][C@H:5]1[CH2:17][OH:18]
Reactant: Cc1c([C@H](O)CN2CCN(C(=O)OC(C)(C)C)C[C@H]2CO)ccc2c1COC2=O
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c([C@H](O)CN2CCN(C(=O)OCc3ccccc3)C[C@H]2CO)ccc2c1COC2=O

Procedure:
To a solution of (S)-tert-butyl 4-((S)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-(hydroxymethyl)piperazine-1-carboxylate (2.57 g, 6.32 mmol) in methylene chloride (3 mL) was added trifluoroacetic acid (10 mL, 130 mmol) at rt for 1 h. After removing the volatiles under reduced pressure the residue was dissolved in methylene chloride (100 mL). To the above solution was added triethylamine (4.40 mL, 31.6 mmol) and benzyl chloroformate (0.95 mL, 6.64 mmol) at 0° C. for 0.5 h. The reaction was quenched by water followed by addition of saturated sodium carbonate. The mixture was extracted with methylene chloride, dried over sodium sulfate, concentrated and the residue was purified by MPLC on a Biotage system using 40-100% EtOAc/hexane to give the title compound. LC/MS: (M+1)+: 441.11.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([NH2:12])=[N:6][NH:7]2.CC(N(CC1C=CC=C(CN2C3C(=C(C(=O)C)C=CC=3)C(NS(C3SC(Cl)=CC=3)(=O)=O)=N2)C=1)C(=O)[O-])(C)C.[OH-].[K+].Br[CH2:54][C:55]1[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[C:57]([F:63])[CH:56]=1>CS(C)=O.C(OCC)(=O)C.ClCCl>[F:63][C:57]1[CH:56]=[C:55]([CH2:54][N:7]2[C:8]3[C:4](=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][CH:9]=3)[C:5]([NH2:12])=[N:6]2)[CH:60]=[CH:59][C:58]=1[O:61][CH3:62]
Reactant: COc1ccc(CBr)cc1F
Reactant: COc1cccc2[nH]nc(N)c12
Agent: CC(=O)c1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN(C(=O)[O-])C(C)(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1ccc(Cn2nc(N)c3c(OC)cccc32)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
4-(Methyloxy)-1H-indazol-3-amine (for a preparation see Intermediate 1) (490 mg, 3 mmol) and potassium hydroxide (185 mg, 3.30 mmol) were dissolved in DMSO (30 mL). The reaction was left to stir for 30 min, before 4-(bromomethyl)-2-fluoro-1-(methyloxy)benzene (657 mg, 3.00 mmol) was added to the reaction mixture and stirred for 1 h at room temperature under nitrogen. The reaction mixture was diluted with ethyl acetate (250 mL) and washed with water (2×250 mL) and brine (250 mL). The organic layer was dried over anhydrous magnesium sulphate and filtered before being evaporated in vacuo to afford a brown oil. The residue was loaded in dichloromethane on a silica 100 g cartridge and purified by chromatography on Flashmaster using a 0-100% ethyl acetate-dichloromethane over 40 min. The appropriate fractions were combined and evaporated in vacuo and the residue re-purified by chromatography on silica 70 g using a 0-50% ethyl acetate-dichloromethane over 40 min. The appropriate fractions were combined and evaporated in vacuo to give the title compound (432 mg, 48%) as an off-white solid. LCMS (System A) RT=0.96 min, ES+ve m/z 302 (M+H)+.
Reaction SMILES: [CH3:1][C:2](=O)[C:3](=[N:7]O)[C:4](=[O:6])[CH3:5].[Cl:10][C:11]1[C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=[C:13]([CH3:19])[N:12]=1.O.C>C(#N)C>[Cl:10][C:11]1[C:16]([C:17]2[NH:18][C:2]([CH3:1])=[C:3]([C:4](=[O:6])[CH3:5])[N:7]=2)=[CH:15][CH:14]=[C:13]([CH3:19])[N:12]=1
Reactant: Cc1ccc(CN)c(Cl)n1
Reactant: CC(=O)C(=NO)C(C)=O
Solvent: CC#N
Solvent: O
Product: CC(=O)c1nc(-c2ccc(C)nc2Cl)[nH]c1C
Temperature: 5 °C
Reaction time: 4 h
Yield: 18.5 %

Procedure:
A mixture of 0.7 g of 2,3,4-pentanetrione 3-oxime and 0.9 g of 2-chloro-6-methyl-3-pyridylmethylamine in 50 ml of acetonitrile was stirred at the reflux temperature for 4 hours. The reaction mixture was evaporated in vacuo to give an oil. The oil was boiled in 50 ml. of water, treated with activated charcoal and filtered. The filtrate was cooled at 5° C. to yield a precipitate. The precipitate was collected, washed with cold water and dried to give 0.25 g of the product of the Example as a white solid, mp 156°-158° C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:16][CH2:15][C:13](=O)[CH2:12][CH2:11]1)=[O:7])([CH3:4])[CH3:3].CCN(S(F)(F)[F:23])CC>C1COCC1>[C:2]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH:10]1[CH2:16][CH2:15][C:13]([F:23])=[CH:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)OC(=O)NCC1CCC(=O)CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC1CC=C(F)CC1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
4-N-Boc-aminomethyl cyclohexanone (4.95 g, 21.8 mmol) was dissolved in THF (80 mL). DAST (4.3 mL, 32.7 mmol) was added dropwise and the solution was stirred at 50° C. for 5 h. The solvent was concentrated and the product purified by flash chromatography on silica gel using hexanes/EtOAc (3:1) as eluent. Yield: 1.62 g (30%). 1H NMR (400 MHz, CDCl3) δ 1.36-1.42 (m, 1 H), 1.44 (s, 9 H), 1.70-1.80 (m, 2 H), 1.82-1.90 (m, 1 H), 2.09-2.17 (m, 1 H), 2.17-2.29 (m, 2 H), 3.04-3.11 (m, 2 H), 4.61 (s, 1 H), 5.11-5.19 (m, 1 H).
Reaction SMILES: C(OC1C=C(C2N3C(CC(=O)N([CH2:29][C:30]([N:32]([CH:41]([CH3:43])[CH3:42])[C:33]4[CH:34]=[N:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=4)=[O:31])C4C=CC=CC=43)=NN=2)C=CC=1)C1C=CC=CC=1.N1C2C(=CC=CC=2)C(C=O)=C1>>[CH:41]([N:32]([C:33]1[CH:34]=[N:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=1)[C:30](=[O:31])[CH3:29])([CH3:42])[CH3:43]
Reactant: COc1ccc(N(C(=O)CN2C(=O)Cc3nnc(-c4cccc(OCc5ccccc5)c4)n3-c3ccccc32)C(C)C)cn1
Agent: O=Cc1c[nH]c2ccccc12
Product: COc1ccc(N(C(C)=O)C(C)C)cn1

Procedure:
Following the procedure described for Example 1(A), Step A, 2-[1-(3-benzyloxy-phenyl)-5-oxo-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide (Preparation 6) (129 mg, 0.219 mmol) was condensed with 1H-indole-3-carbaldehyde (70 mg, 0.48 mmol). Purification by medium pressure chromatography eluting with a solvent gradient (10% EtOAc in hexanes to 100% EtOAc) yielded 60 mg of 2-[1-(3-benzyloxy-phenyl)-4-1H-indol-3-ylmethylene)-5-oxo-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide. 1H NMR (CD3OD) δ 8.13 (m, 1H), 7.64 (m, 2H), 7.23-7.48 (m, 3H), 7.13 (m, 3H), 6.93 (m, 2H), 4.94 (m, 2H), 4.85 (m, 1H), 4.63 (m, 1H), 4.20-4.40 (m, 1H), 3.96 (m, 1H), 3.85 (d, 1H), 0.90-1.05 (m, 6H); MS 716.5 (M+1), 714.6 (M−1)
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[OH2:11].CC(O)=[O:14]>>[Br:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([N+:6]([O-:14])=[O:11])=[C:4]([F:10])[CH:3]=1
Reactant: CC(=O)O
Reactant: O
Reactant: Nc1c(F)cc(Br)cc1F
Product: O=[N+]([O-])c1c(F)cc(Br)cc1F
Temperature: 70 °C

Procedure:
A solution of 4-bromo-2,6-difluoroaniline (240 mmol) in AcOH (150 mL) was added dropwise to a suspension of NaBO3.4 H2O (325 mmol) in AcOH (450 mL) at 70° C. during 30 min. Another 2080 mmol of NaBO3.4 H2O were added over 5 h to the mixture. During this period the mixture was stirred at 70° C. The mixture was poured into water and extracted with Et2O. The organic layer was combined with another Et2O solution obtained from another reaction using the same conditions described above. The mixture was concentrated. A precipitate was formed and separated by filtration. The filtrate was concentrated to afford the desired product after flash column chromatography (SiO2, petroleum ether).
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])(=[O:4])=[O:3].O.[NH3:15]>CO>[CH:11]1[CH:10]=[C:6]2[C:7]([NH:15][S:2](=[O:4])(=[O:3])[C:5]2=[CH:13][CH:12]=1)=[O:8]
Reactant: N
Reactant: O=C(Cl)c1ccccc1S(=O)(=O)Cl
Solvent: CO
Solvent: O
Product: O=C1NS(=O)(=O)c2ccccc21
Yield: 93 %

Procedure:
A 20 g amount of the mixture of o-chlorosulfonylbenzoylchloride and dichlorotolylsultone was added dropwise to 40 ml of methanol with stirring at 15°-20° C. and the mixture was stirred and reacted for 1 hour. After the reaction, the reaction mixture was added dropwise to 35 g of 8% ammonia water with stirring at 20°-25° C., and the reaction mixture was kept for one night. Then, methanol was removed by distillation from the reaction mixture under a reduced pressure, and hydrochloric acid was added to the residual product to adjust pH to 1-2. The precipitated crystals were filtered and washed with water and dried, to obtain 14.3 g of white crystals of o-sulfobenzimide having a melting point of 227°-228° C. (yield of 93%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH2:8].[C:9](#[N:12])[CH:10]=[CH2:11]>>[C:9]([CH2:10][CH2:11][NH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH2:8])#[N:12]
Reactant: C=CC#N
Reactant: NC1CCCCC1N
Product: N#CCCNC1CCCCC1N

Procedure:
1,2-diaminocyclohexane (1) is cyanoethylated with acrylonitrile in the presence of an acid catalyst (Equation 1) with one mole ##STR17## of acrylonitrile the monocyanoethylated product, N-(2-Cyanoethyl)-1,2-cyclohexanediamine, (2), is formed, two moles of acrylonitrile react to give the dicyanoethylated product, N,N'-di-(2-cyanoethyl)-1,2-diaminocyclohexane, (3).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].[CH3:9][OH:10]>>[CH3:9][O:10][CH:6]1[CH2:5][CH2:4][CH2:3][C:2](=[O:7])[CH2:1]1
Reactant: CO
Reactant: O=C1CCCCC1=O
Product: COC1CCCC(=O)C1

Procedure:
If methanol is used as solvent (example 5), which esterifies with cyclohexane-dione to yield 3-methoxy-cyclo-hexanone, resorcinol-monomethyl ether is formed as by-product.
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:34][O:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:5]([NH:7][CH:8]1[C:32](=[O:33])[N:10]2[C:11]([C:16]([O:18][CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[S:17])=[C:12]([CH3:15])[CH2:13][S:14][C@H:9]12)=[O:6].[NH2:42][C:43]([NH2:45])=[S:44].C([O-])(=O)C.[Na+].C(OCC)(=O)C>O1CCCC1.O>[NH2:45][C:43]1[S:44][CH:2]=[C:3]([C:4](=[N:34][O:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:5]([NH:7][CH:8]2[C:32](=[O:33])[N:10]3[C:11]([C:16]([O:18][CH:19]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[S:17])=[C:12]([CH3:15])[CH2:13][S:14][C@H:9]23)=[O:6])[N:42]=1
Reactant: COC(=O)CON=C(C(=O)CCl)C(=O)NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(C)CS[C@H]12
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(C)CS[C@H]12)c1csc(N)n1
Reaction time: 2 h
Yield: 89.1 %

Procedure:
A mixture of benzhydryl 7-[4-chloro-2-(methoxycarbonylmethoxyimino)-3-oxobutyramido]-3-methylthio-3-cephem-4-carboxylate (syn isomer) (18.97 g), thiourea (4.56 g) and sodium acetate (7.38 g) in tetrahydrofuran (150 ml) and water (80 ml) was stirred at 40° to 45° C. for 2 hours. Ethyl acetate (300 ml) was added to the reaction mixture at room temperature and the organic layer was separated. The organic layer was washed with brine and dried over magnesium sulfate. The solution was evaporated and the residue was triturated with ether to give benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-(methoxycarbonylmethoxyimino)acetamido]-3-methylthio-3-cephem-4-carboxylate (syn isomer) (17.5 g).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)([O-:3])=[O:2].[Cl-].[Br:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[CH:17]=[N+:18]([CH3:20])[CH3:19].BrC1C=CC=CC=1C=O.CNC>>[Br:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[CH:17]([N:18]([CH3:20])[CH3:19])[C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])[NH:8][CH:7]=1
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Reactant: C[N+](C)=Cc1ccccc1Br
Agent: CNC
Agent: O=Cc1ccccc1Br
Agent: [Cl-]
Product: CN(C)C(c1ccccc1Br)c1c[nH]c2cccc([N+](=O)[O-])c12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 4-nitroindole and (2-bromo-benzylidene)-dimethyl-ammonium chloride, which had been prepared in accordance with example 24 from 2-bromo-benzaldehyde and dimethylamine.